Heart Failure is a clinical syndrome characterized by progressive ventricular dilatation, depressed cardiac function and premature death. Importantly, variation in the development of heart failure and in the long-term survival irrespective of etiology indicates that additional unidentified genetic factors play a significant role in the phenotypic expression. Unfortunately, these modifier genes have been recalcitrant to direct identification in human populations. In this regard, genetic studies in animals models of disease can identify candidate modifier genes and provide an insight on the genetic interactions that cause phenotypic variation in the humans. The goal of this proposal is to identify genetic modifiers of human heart failure. To accomplish this goal we will use a well-characterized murine model of heart failure created by the overexpression of a calsequestrin (CSQ) transgene to simulate a monogenetic disorder of inherited dilated cardiomyopathy. The phenotype of the CSQ model demonstrates many of the "hallmark" features of dilated cardiomyopathy including progressive cardiac dysfunction, shortened lifespan and abnormalities in beta-adrenergic receptor signaling. Although the model is not one caused by a natural occurring single-gene mutation in humans, it is one that recapitulates the human heart failure phenotype and importantly, is highly dependent on the genetic background. Accordingly, the goal of this project is to use the CSQ mouse to identify modifier genes that contribute to the severity of heart failure in the human population. The following specific aims are proposed: 1) to identify modifier genes in the CSQ mouse model of heart failure that confer susceptibility to premature death. Quantitative Trait Loci mapping has already shown strong linkage of survival to a narrow region on chromosome 2. 2) to identify modifier genes in the CSQ mouse model of heart failure that delay susceptibility to both cardiac dysfunction and premature death. Quantitative Trait Loci mapping has already shown strong linkage of cardiac function and survival to a broad region on chromosome 3 and 8. 3) to test whether modifier genes influence phenotypic variation in human heart failure, we will examine whether genetic polymorphisms identified in the mouse correlate with outcome in patient populations with heart failure. Genetic epidemiology will be performed in collaboration with the Duke Center for Human Genetics.